Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-...
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| Formato: | Articulo |
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2023
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| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/152249 |
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I19-R120-10915-1522492023-08-29T18:27:33Z http://sedici.unlp.edu.ar/handle/10915/152249 Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease Prada Gori, Denis Nihuel Ruatta, Santiago Fló, Martín Alberca, Lucas Nicolás Bellera, Carolina Leticia Park, Soonju Heo, Jinyeong Lee, Honggun Paul Park, Kyu-Ho Pritsch, Otto Shum, David Comini, Marcelo A. Talevi, Alan 2023 2023-04-27T17:37:53Z en Biología Atpenin Tinostamustine In silico screening Cysteine proteases COVID-19 Drug repositioning SARS-CoV-2 The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV- 2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 μM and 4 μM, respectively) but not the papain-like protease of SARSCoV- 2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARSCoV- 2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency. Laboratorio de Investigación y Desarrollo de Bioactivos Articulo Articulo http://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International (CC BY 4.0) application/pdf |
| institution |
Universidad Nacional de La Plata |
| institution_str |
I-19 |
| repository_str |
R-120 |
| collection |
SEDICI (UNLP) |
| language |
Inglés |
| topic |
Biología Atpenin Tinostamustine In silico screening Cysteine proteases COVID-19 Drug repositioning SARS-CoV-2 |
| spellingShingle |
Biología Atpenin Tinostamustine In silico screening Cysteine proteases COVID-19 Drug repositioning SARS-CoV-2 Prada Gori, Denis Nihuel Ruatta, Santiago Fló, Martín Alberca, Lucas Nicolás Bellera, Carolina Leticia Park, Soonju Heo, Jinyeong Lee, Honggun Paul Park, Kyu-Ho Pritsch, Otto Shum, David Comini, Marcelo A. Talevi, Alan Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| topic_facet |
Biología Atpenin Tinostamustine In silico screening Cysteine proteases COVID-19 Drug repositioning SARS-CoV-2 |
| description |
The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV- 2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro.
From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 μM and 4 μM, respectively) but not the papain-like protease of SARSCoV- 2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARSCoV- 2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors.
Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency. |
| format |
Articulo Articulo |
| author |
Prada Gori, Denis Nihuel Ruatta, Santiago Fló, Martín Alberca, Lucas Nicolás Bellera, Carolina Leticia Park, Soonju Heo, Jinyeong Lee, Honggun Paul Park, Kyu-Ho Pritsch, Otto Shum, David Comini, Marcelo A. Talevi, Alan |
| author_facet |
Prada Gori, Denis Nihuel Ruatta, Santiago Fló, Martín Alberca, Lucas Nicolás Bellera, Carolina Leticia Park, Soonju Heo, Jinyeong Lee, Honggun Paul Park, Kyu-Ho Pritsch, Otto Shum, David Comini, Marcelo A. Talevi, Alan |
| author_sort |
Prada Gori, Denis Nihuel |
| title |
Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| title_short |
Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| title_full |
Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| title_fullStr |
Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| title_full_unstemmed |
Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease |
| title_sort |
drug repurposing screening validated by experimental assays identifies two clinical drugs targeting sars-cov-2 main protease |
| publishDate |
2023 |
| url |
http://sedici.unlp.edu.ar/handle/10915/152249 |
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